Ataxia telangiectasia and Rad-3-related (ATR) is a member of the phosphatidylinositol kinase-related protein family that includes ATM and DNA-PK. These kinases are essential for signaling the presence of DNA damage or replication blocks and activating cell cycle checkpoints (Durocher and Jackson, 2001; Shiloh, 2001). ATR is the sequence and functional homologue of the Rad3 and Mec1 checkpoint proteins from S. pombe and S. cerevisiae respectively (Bentley et al., 1996; Cimprich et al., 1996).
The function of ATM has been extensively studied in cell lines derived from A-T patients that lack expression of the ATM protein. The lack of comparable cell lines for ATR has impaired analysis of its specific activities. Overexpression of catalytically-inactive versions of ATR indicates that it is required for checkpoint responses following treatment of cells with agents that cause various forms of DNA damage or block replication (Wright et al., 1998; Cliby et al., 1998; Tibbetts et al., 1999; Tibbetts et al., 2000). Furthermore, homozygous deletion of ATR in mice causes early embryonic lethality, suggesting that ATR has essential functions during development (Brown and Baltimore, 2000; de Klein et al., 2000).
Rad3 and Mec1 function in cooperation with the Rad26 and DDC2 (also called LCD1 or PIE1) proteins respectively (Edwards et al., 1999; Paciotti et al., 2000; Rouse and Jackson, 2000; Wakayama et al., 2001). Rad26 binds to and is phosphorylated by Rad3, whereas DDC2 binds to and is phosphorylated by Mec1. Mutations in either Rad3 or Rad26 yield almost identical phenotypes, as do mutations in either Mec1 or DDC2. As yet, the functional roles of Rad26 and DDC2 are unclear. However, Rad3 and DDC2 are essential for transducing checkpoint signals to downstream proteins such as the Chk1 protein kinase (Edwards et al., 1999; Paciotti et al., 2000; Rouse and Jackson, 2000; Wakayama et al., 2001).
The present invention is directed to an ATR-interaction gene product defined as ATRIP, and compositions and methods related thereto are described herein.